Cervical cancer is one of the most common malignancies affecting women worldwide and a major cause of cancer death for women globally. Radiotherapy combined with cisplatin is the treatment of choice at the locally advanced stages. Improved therapy is needed, since more than 30% of the patients show progressive disease within 5 years after diagnosis and treatment related side effects to organs within the pelvis are frequent. Tumor stage, size, and lymph node involvement are the most powerful markers of aggressive disease, but do not fully account for the observed variability in outcome and are not biologically founded.
A better handling of the disease may be provided by the discovery of efficient biomarkers for therapeutic planning and intervention, but requires more insight into the mechanisms underlying cervical carcinogenesis and treatment relapse.
During carcinogenesis, genetic and epigenetic alterations drive the evolution of tumor towards increased malignancy and treatment resistance. The changes enable tumor cells to overcome microenvironmental constraints, sustain proliferation, and invade adjacent tissues and distinct organs. Gene dosage alterations like gains and losses regulate the expression of genes and are motive forces for this evolution.
Tumor cells bearing an increasing number of gains and losses successively emerge and are selected for based on the growth advantage caused by the genetic changes. Discovery and functional assessment of gene dosage alterations involved in carcinogenesis are therefore essential for understanding the biology of the disease.
At the locally advanced stages of cervical cancer, numerous gene dosage alterations and severe aneuploidy are frequently seen. Moreover, pronounced intratumor heterogeneity in the gains and losses exists within the tumors, reflecting a high genetic instability.
The consequences of these alterations for the tumor phenotype are difficult to predict, since large chromosomal regions involving multiple genes are generally affected and some aberrations may be random events without biological significance. Genome wide screening of DNA copy numbers in a decent number of patients enables identification of recurrent gene dosage alterations; i.e., alterations characteristic of the disease, and alterations associated with the clinical outcome, which are likely to be important in carcinogenesis and treatment resistance.
Combining the data with expression profiles of the same tumors reveals the genes that are regulated primarily by the genetic events. The potential of this integrative strategy was recently demonstrated in a study on 15 early stage cervical cancers, where genes affected by aberrations on 1q, 3q, 11q, and 20q were reported.
Genetic events promoting tumor evolution and treatment resistance have, however, not been explored on a genome wide scale, and their biological meaning has not been addressed.